title: A genome-wide investigation of copy number variation in patients with sporadic brain arteriovenous malformation.
abstract: BACKGROUND
  Brain arteriovenous malformations (BAVM) are clusters of abnormal blood vessels, with shunting of blood from the arterial to venous circulation and a high risk of rupture and intracranial hemorrhage. Most BAVMs are sporadic, but also occur in patients with Hereditary Hemorrhagic Telangiectasia, a Mendelian disorder caused by mutations in genes in the transforming growth factor beta (TGFβ) signaling pathway.
  
  
  METHODS
  To investigate whether copy number variations (CNVs) contribute to risk of sporadic BAVM, we performed a genome-wide association study in 371 sporadic BAVM cases and 563 healthy controls, all Caucasian. Cases and controls were genotyped using the Affymetrix 6.0 array. CNVs were called using the PennCNV and Birdsuite algorithms and analyzed via segment-based and gene-based approaches. Common and rare CNVs were evaluated for association with BAVM.
  
  
  RESULTS
  A CNV region on 1p36.13, containing the neuroblastoma breakpoint family, member 1 gene (NBPF1), was significantly enriched with duplications in BAVM cases compared to controls (P = 2.2×10(-9)); NBPF1 was also significantly associated with BAVM in gene-based analysis using both PennCNV and Birdsuite. We experimentally validated the 1p36.13 duplication; however, the association did not replicate in an independent cohort of 184 sporadic BAVM cases and 182 controls (OR = 0.81, P = 0.8). Rare CNV analysis did not identify genes significantly associated with BAVM.
  
  
  CONCLUSIONS
  We did not identify common CNVs associated with sporadic BAVM that replicated in an independent cohort. Replication in larger cohorts is required to elucidate the possible role of common or rare CNVs in BAVM pathogenesis.
authors.affiliation: Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Nasrine
authors.initials: N
authors.lastname: Bendjilali
authors.forename: Helen
authors.initials: H
authors.lastname: Kim
authors.forename: Shantel
authors.initials: S
authors.lastname: Weinsheimer
authors.forename: Diana E
authors.initials: DE
authors.lastname: Guo
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Zaroff
authors.forename: Stephen
authors.initials: S
authors.lastname: Sidney
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lawton
authors.forename: Charles E
authors.initials: CE
authors.lastname: McCulloch
authors.forename: Bobby P C
authors.initials: BP
authors.lastname: Koeleman
authors.forename: Catharina J M
authors.initials: CJ
authors.lastname: Klijn
authors.forename: William L
authors.initials: WL
authors.lastname: Young
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
mesh_terms: D000328:Adult; D000465:Algorithms; D056915:DNA Copy Number Variations; D005260:Female; D063990:Gene Ontology; D055106:Genome-Wide Association Study; D006801:Humans; D002538:Intracranial Arteriovenous Malformations / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D058977:Molecular Sequence Annotation; D015203:Reproducibility of Results